Lateral gene transfer between Humans and Malarial Parasite P.vivax
Introduction The horizontal transfer of DNA between different organisms is a major force shaping thegenomes of prokaryotes, but is considered to have a minor role in eukaryotes, with only a handful of known mostly of limited size examples. The Daniel et al (2011) here describe evidence for lateral gene transfer from humans and malrial parasite'' P.vivax (Deitsch et al. 2001). They used computational approach by comparing the plasmodium genomes which they divided into smaller fragments and comparing it with human genome. The identified fragments were then enriched for mRNA coding sequences and genes that are known to be functionally important for P. vivax, including nitric oxide synthase 1 (neuronal) adaptor and Interleukin-1 family, suggesting a functional role.Their results indicate that the Plasmodium vivax genome is interlaced with multiple DNA fragments acquired via horizontal transfer from humans. Daniel et al arugue that these results could be important on understanding the how the immune system interacts with plasmodium. Background Plasmodium the causative organism of malaria spends half of tis life cylce in mosquitoes and vertebrate hosts in a species specific manner and very few species of plasmodium are known to infect humans and among these ''P. falciparum, the cause of most human infections and deaths;'' P. vivax'', is responsible for recurring (quartan) malaria; and Plasmodium knowlesi, that infects mainly macaques but has been shown to infect humans both naturally and artificially .For the first time it was shown that cross-kingdom HGT from humans is likely to have had a significant, and probably functional, contribution to the P. vivax genome. Methods Genomes of the plasmodium species were divided into 60 letters long fragments by inserting unique identifiers and was compared to the human genome using BLASTN. These genomes included the common human infectious P.falciparum and P.vivax, the rarely human infectious P. knowlesi the primate infectious'' P.reichenowi'', as wells as P.gallinaceum, P. yoelii, P. berghei, and P. chabaudi. The Plasmodium fragment queries were also compared to the other Plasmodium genomes used in this study to remove highly conserved sequences and a comparison to the mouse genome was performed, to help in delimiting the origin of the HGT sequences . The remaining sequences, originating from a Plasmodium genome and having close homologs in the human genome and not other Plasmodium genome tested, were considered PHE events (Fig 1B). P. vivax resulted in 3009 sequences with close homologs in the human genome, of these 2966 (98.6%) showed greater similarity to the human genome then to any other Plasmodium examined (Fig. 1C). Contamination issues: A major concern when searching for HGT in parasites is the contamination of genome nucleotide databases with sequence information derived from genetic material from the host. To verify this is not due to contamination, Daniel et al used 10 primer sets to identify features combining sequences similar to human DNA with characteristics not found in the human genome. For example, their primer set 2 which has similarity to the human genome, with a deletion in the middle of the region of similarity (Fig. 3B) and in case of a contamination, they hypotheisized that it wuold be unlikely that the same deletion will be seen in an independently derived genomic DNA sample. Verification: Five independent lines of evidence suggest that the results obtained were due to errors in the sequencing and assemble of the P. vivax genome, but genuine HGT events: (i) P. vivax was isolated for sequencing from squirrel monkeys (Saimiri boliviensis boliviensis). Of the PHE found, only 18% have highly similar sequences (e-value < 10-7) in the squirrel monkey geno me, indicating that host contamination is unlikely. (ii) PHE sequences from the P. vivax genome are 96% similar to human, (PHE with a squirrel monkey homolog show 93.8% similarity), while the control genomes, that show >99% similarity between Plasmodium and either human or host sequences. This percent of identity is below the expected similarity for a contamination. (iii) Both cumulative PHE e-values, plotted on a logarithmic scale, and percent identity, appear almost linear. This is consistent with multiple HGT events, where integrated fragments accumulate mutations over time, but not with a contamination (Fig 3C, D) (iv) The sequences found are enriched for mRNA (9.5% compared to 1.1% expected(Venter et al. 2001); P < 3×10-14, cumulative binomial distribution). (v) Results are enrichement (P < 6×10-12;benjamini correction < 4×10-8) for IL1 familliy. Mechanisms for Human Gene Tansfer (HGT): 1) DNA fragments can penetrate the membrane ruptures 2) Elements of Viral Origin can transfer specific DNA and RNA Molecules across the membranes 3) Selfish element could leave the host genome and get incorporated into foreign DNA. Results: 1) S60429 was found to be closely related to 13 other PHE contigs and most of the S60429 was mapped to Nitric Oxide synthase1 Adptor. Nitric oxide (NO) si known to play a major role in host-parasite interaction, but its role remains controversial, it could have a protective effect against malaria (Anstey etal 1999) or parasite induced NO production may be the cause of parasite related anemia. 2) A global view of the human homologs of PHE revealed an enrichment for Interleukin-1 (IL-1) family that are known to be essential for protection against infections. A polymorphism in IL-1 that results in receptor antagonist is mapped to a PHE and is involved in susceptibility to malaria. These results imply that HGT events in plasmodium were fixed via functional selection and noth much is known how the incorporated DNA serves the parasite. 1) The possible ways these fragments could serve as, but might serve to imitate protein domains or serve as non coding RNA expression regulators. 2) Could use the DNA from its host to manipulate immune response pathways deleterious to parasite persistence and doing so, it might manage to cope with new genetic adaptations. References 1 Bar,Daniel. Evidence of Massive Horizontal Gene Transfer Between Humans and Plasmodium vivax. Nature Precedings (2011). 2 Anstey, N.M,D.L. Granger, M.Y.Hassanali, et al 1999. Nitric oxide , malaria and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria exposed children. Am J Trop Med Hyg 61(2): 249‐52 .